NO156410B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 6ALFA METHYLPREDNISOLON DERIVATIVES. - Google Patents

Abstract

Novel 6 alpha -methylprednisolone derivatives of the general formula I <IMAGE> (in which R1 represents C2-C6-I-oxoalkyl or benzoyl and R2 represents H, C2-C6- I-oxoalkyl or benzoyl) and a process for their manufacture. The novel compounds are useful in the treatment of skin disorders and of allergic disorders of the respiratory and intestinal tracts.

Description

The present invention relates to an analog method

for the production of therapeutically active 6a-methylprednisolone-

. derivatives of general formula:

in which

denotes a 1-oxoalkyl radical with 2 to 6 carbon atoms or a benzoyl radical, and

1*2 denotes hydrogen, a 1-oxoalkyl radical with 2 to 6 carbon

atoms or a benzoyl residue.

The new 6oc-methylprednisolone derivatives of general

formula I can as 1-oxoalkyl groups R, and R2

with 2 to 6 carbon atoms, for example carrying an acetyl group,

a propionyl group, a butyryl group, an isobutyryl group,

a valeryl group, a 3-methylbutyryl group, a trimethyl-

acetyl group or a hexanoyl group.

It is found that the new derivs

of 6a-methylprednisolone surprisingly often with topical administration

trering exhibits a significantly stronger activity than the previously known 6a-methylprednisolone derivatives. This effect

potency is even often considerably stronger than the difluorinated "elecorticoids" such as 6a,9a-difluoro-li<p->hydroxy-16a-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione.

When administered systemically, these 6a-methylprednisolone derivatives are surprisingly often less effective than the corresponding previously known 6<x-methylprednisolone derivatives

spirit level.

The new 6a-methylprednisolone derivatives of general

formula I is thus suitable in combination with the usual carrier substances within galenic pharmacy

local treatment of contact dermatitis, eczema of various kinds, neurodermatoses, erythroderma, burns, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.

The topical activity of the compounds was determined by means of the following vasoconstriction test: The test was performed on 8 healthy subjects of both sexes who had not received any local corticosteroid treatment in the last two weeks. After removal of the Stratum corneum to Stratum lucidum on the subjects' backs (20-40 tesafilm tears), 0.1 g of the preparation was applied to a 4 cm 2 field without an occlusive dressing. To ensure that the same preparation was administered on an identical area of skin, these were applied in rotating order.

Vasoconstriction was assessed visually after 8 hours according to the following levels of efficacy: 1 = absolute bleaching, 2 = slight residual erythema, 3 = erythema of medium degree, red staining intensity in the middle area of torn, untreated and undamaged skin, 4 = erythema with slight bleaching, 5 = no fading or strengthening of the erythemas.

The individual assessments were noted.

In each series of experiments, diflucortolone-21-valerianate ( = 6a, 9cx-difluoro-llf3-hydroxy-16a-methyl-21-valeryloxy-1,4-pregnadiene-3,20-

dione = DFV).

The difference A in the average effectiveness degrees of DFV and test substance obtained in the individual test series was determined. Positive deviation A shows a favorable, and negative deviation shows an unfavorable effect of the test substances in comparison with DFV.

In the following table, the observed test results are indicated, which were obtained when the test persons were treated with a preparation containing 0.001% active substance.

The systemic side effects were determined using the thymolysis test, which was performed as follows:

SPF rats weighing 70 to 110 g were adrenalectomized under ether anesthesia. 6 animals formed a test group that . over n days received a solution of 2 ml of a 0.1% test substance solution on a 5x5 cm skin area. On the following day, the animals were euthanized and their thymus weight was determined. The control animals were treated in the same way, but received only 2 ml of active substance-free solution. From the obtained thymus weights, the percentage thymolytic effect was calculated in the usual way.

The following table indicates the obtained test results.

The preparation of the medicinal preparations takes place in the usual way, as the active ingredient with suitable additives is transferred into the desired administration form, such as e.g. solutions, lotions, ointments, creams or plasters. In the drugs formulated in this way, the active substance concentration depends on the form of administration. For lotions and ointments, an active substance concentration of 0.001 to 1% is preferably used.

Furthermore, the new compounds, possibly in combination with usual carriers and excipients, are also well suited for the production of inhalants, which can be used for the treatment of allergic diseases in the respiratory tract, such as e.g. bronchial asthma or rhinitis.

Furthermore, the new corticoids are also suitable in the form of capsules, tablets or dragées, which preferably contain 10 to 200 mg of active ingredient and which are administered orally, or in the form of suspensions which preferably contain 100 to 500 mg of active ingredient per unit dose and which is administered rectally. The compounds can also be used for the treatment of allergic diseases in the intestinal tract, such as ulcerative colitis and granulomatous colitis.

The analogue method according to the invention is characterized by the fact that from a corticoid of general formula:

in which

and R 2 have the meanings given above, hydrogen bromide is split off with lithium chloride.

The method can be carried out under the conditions described, for example, in German patent applications no. 26 45 104, 26 45 105, 23 40 591 and 19 58 549, as well as in US patent document no. 3 383 394 or in J. Amer. Chem. Soc, 79.” (1957), 1515.

The following examples illustrate the invention.

Example 1

A) A suspension of 34.0 g of 21-acetoxy-9o-bromo-113,17-dihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione in 1.36 l of methanol and 120 ml of 70%- 1 g of perchloric acid was stirred for 20 hours at room temperature. After ice water precipitation, the precipitate was separated, washed neutrally with water and dried in a vacuum oven.

28.3 g of 9α-bromo-lip,17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione were obtained. Temp. 159-160°C.

B) From a solution of 4.3 g of 9a-bromo-11,17,21-trihydroxy-6<x-methyl-1,4-pregnadiene-3,20-dione and 430 mg of pyridinium tosylate in 34.5 ml of dimethylformamide and 300 ml of benzene was at 130°C

129 ml of benzene distilled over a water separator. To the hot reaction solution, 10.3 ml of ortho-butyric acid trimethylester was added dropwise, and additional benzene and other easily volatile reaction components were then distilled off.

5 ml of pyridine was added and the mixture was evaporated in vacuo to dryness. 9α-bromo-11β-hydroxy-17α,21-(1-methoxybutylidenedioxy)-6α-methyl-1,4-pregnadiene-3,20-dione was isolated as an oil. C) The impure 9α-bromo-113-hydroxy-17α,21-(1-methoxy-butylidenedioxy)-6α-methyl-1,4-pregnadiene-3,20-dione was dissolved in 129 ml of methanol and was stirred with a mixture of 4 6.4 ml 0.1N aqueous acetic acid and 5.2 ml 0.1M aqueous sodium acetate solution for 1 hour at 80°C bath temperature. The solution was evaporated to 1/3 of its volume, poured into water, and the acetic ester extract was washed neutral. After drying and evaporation, the crude product was purified on 200 g of silica gel with a hexane-acetone gradient (0-60% acetone). 3.7 g of 9<x-bromo-17α-butyryloxy-113,21-dihydroxy-6α-methyl-1,4-pregna-diene-3,20-dione were isolated. Temp. 158-159°C. D) A suspension of 3.0 g of 9α-bromo-17α-butyryloxy-113,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione in 60 ml of hexamethylphosphoric triamide was stirred with 3.0 g of lithium chloride for 1 hour at 80°C bath temperature. After ice water precipitation, the residue was filtered off, washed with water, after which the crude product was purified on 105 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone). 938 mg of 17α-butyryloxy-113,21-dihydroxy-6α-methyl-1,4,8-pregnatriene-3,20-dione were isolated as a foam. f0^^ = -53.8°.

Example 2

A) Analogous to example IB), 17.4 g of 9α-bromo-113,17α,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione were reacted with 4 2.0 ml orthobenzoic acid triethyl ester and was then worked up. 9α-bromo-17α,21-(1-ethoxybenzylidenedioxy)-113-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione was isolated as an oil. B) The impure 9α-bromo-17α,21-(1-ethoxybenzylidenedioxy)-113-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione was hydrolyzed and worked up under the conditions described in example 1C ). The crude product was purified on 1 kg of silica gel with a hexane-acetone gradient (0-50% acetone). Yield 12.47 g of 17α-benzoyloxy-9α-bromo-113,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione. Temp. 159°C. C) A solution of 2.0 g of 17a-benzoyloxy-9a-bromo-113,21-dihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione was reacted with 2.0 g of lithium chloride as described in example ID), and was then worked up. The crude product was purified on 105 g of silica gel with a methylene chloride-acetone gradient (0.20% acetone). Yield: 1.2 g of 17α-benzoyloxy-113,21-dihydroxy-6α-methyl-1,4,8-pregnatriene-3,20-dione. Temp. 206-208°C.

Example 3

A) 3.0 g of 17a-benzoyloxy-9a-bromo-11,21-dihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione was stirred in 30 ml of pyridine with 15 ml of acetic anhydride for 3 hours at room temperature . After usual work-up, 3.2 g of 21-acetoxy-17a-benzoyloxy-9a-bromo-11f}-hydroxy-6ct-methyl-1,4-pregnadiene-3,20-dione were obtained. Temp. 172-173°C. B) 3.3 g of 21-acetoxy-17o-benzoyloxy-9a-bromo-113-hydroxy-6a-methyl-1,4-pregnadiene-3,20-dione was reacted analogously to example ID) with 3.3 g of lithium chloride and was then worked up. The crude product was purified on 200 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 1.78 g of 21-acetoxy-17a-benzoyloxy-113-hydroxy-6ct-methyl-1,4,8-pregnatriene-3,20-dione. Temp. 229-230°C.

Example 4

A) Analogously to example 3A), 3.0 g of 17a-benzoyloxy-9ct-bromo-113,21-dihydroxy-6ct-methyl-1,4-pregnadiene-3,20-dione was reacted with propionic anhydride and was then worked up. 3.1 g of 17α-benzoyloxy-9α-bromo-113-hydroxy-6α-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione were obtained, m.p. 155-156°C. B) 3.2 g of 17a-benzoyloxy-9o-bromo-113-hydroxy-6a-methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione were reacted under the conditions described in example ID) with lithium chloride and was then worked up and purified. 1.96 g of 17α-benzoyloxy-113-hydroxy-6α-methyl-21-propionyloxy-1,4,8-pregnatriene-3,20-dione were isolated. Temp. 225-226°C.

Claims (1)

Analogous method for the preparation of therapeutically active 6a-methylprednisolone derivatives of general formula: in which R denotes a 1-oxoalkyl radical with 2 to 6 carbon atoms or a benzoyl radical, and R2 denotes hydrogen, a 1-oxoalkyl radical with 2 to 6 carbon atoms or a benzoyl radical, characterized in that from a corticoid of general formula: in which R 1 and R 2 have the meanings given above, hydrogen bromide is split off with lithium chloride.